A windfall year for HCC: The most impactful clinical papers in 2023

INTRODUCTION The year 2023 has been prolific for impactful studies in HCC. The clinical management of HCC, a leading cause of cancer-related mortality worldwide, is challenging across the entire spectrum of the disease, from the detection of early-stage tumors and prevention of cancer recurrence after resection to the treatment of metastatic disease. HCC has an incidence-to-mortality ratio of 0.92, the highest for any solid tumor, and this reflects the limited number of efficacious therapies currently available for this malignancy.1 Between 2008 and 2023, only 4 systemic therapies have been approved as first-line therapy in HCC, on the basis of positive randomized controlled trials (RCTs), and all have been in the advanced-stage HCC setting. Ground-breaking phase III RCTs published in 2023 will however impact the management and clinical outcomes of all stages of HCC. Never have we seen such a windfall for this cancer. These successes have leveraged rapid advances in the fields of genomics and molecular biology that have culminated in the emergence of immunotherapy, including immune checkpoint inhibitors (ICIs) and targeted therapy, several of which have now become standards of care in HCC. Therapeutics in HCC are beginning to come of age. For more than 10 years, only a single first-line systemic therapy was available in HCC. The clinical management of HCC will now look more like that of other common cancers, such as colorectal, breast, and lung cancer, where multiple therapeutics are available for all stages of the cancers. We highlight here the most impactful phase III RCTS published in 2023 for HCC. ADJUVANT THERAPY FOR CURATIVE INTENT RADICAL AND ABLATIVE THERAPIES IN EARLY AND EARLY-INTERMEDIATE STAGES OF HCC While the Barcelona Clinic Liver Cancer (BCLC) staging system advocates surgical resection and ablative therapies only for early-stage HCC described as BCLC stages 0 and A, real-world data shows that curative-intent surgical resection and thermal ablation are used as first-line therapy over a wide range of nonmetastatic HCC.2 This practice is supported by RCT, which demonstrated that surgical resection is superior to trans-arterial chemoembolization (TACE) in BCLC Stage B.3 There has however been no prospectively validated adjuvant therapy after such curative intent resections and ablation. Despite adopting progressive surgical techniques in line with the principles of surgical oncology, recurrence rates remain high both within and outside of early-stage HCC. Recurrence after curative-intent surgical resection is characterized by a bimodal pattern: early recurrence, which peaks at around 12 months, arising from micro-metastases from the original or index tumor, and a lower incidence late recurrence, which peaks at between 4 and 5 years that is related to de novo cancer arising from the underlying liver parenchymal disease.4 However, without validated adjuvant therapy, the current standard of care following surgical resection or thermal ablation with curative intent is close surveillance. The IMbrave050 trial investigated the use of atezolizumab and bevacizumab as adjuvant therapy in patients with HCC at risk of tumor recurrence after curative-intent surgical resection or thermal ablation, based on known risk factors, including tumor size, number, vascular invasion, and tumor differentiation.5 At the first predetermined event-driven interim analysis, the IMBrave050 met its primary end point and showed improved recurrence-free survival (HR 0.72, 95% CI: 0.53–0.98, p = 0.012) with adjuvant atezolizumab and bevacizumab compared to close surveillance after a median follow-up of only 17.4 months. Twelve-month landmark analysis showed that disease recurrence was 33% lower in the atezolizumab plus bevacizumab group than in the active surveillance group (20% vs. 34%, HR = 0.67, 95% CI: 0.52-0.88) p value=0.003). Overall survival (OS) data was however immature (HR=1.42, 95% CI: 0.80–2.54) and another 3–5 years of follow-up is estimated to be required for these data to mature. Patients treated with atezolizumab and bevacizumab had more adverse effects, notably proteinuria, hypertension, decreased platelets, and derangements of liver function test. These adverse effects are however asymptomatic to the patients, and the median duration of treatment was high at 11.2 months for atezolizumab and 11 months for bevacizumab, respectively. Cross-over to the treatment arm was allowed for the close observation arm either at the point of recurrence or following a second resection or thermal ablation, and at the first interim analysis, 61% have crossed over. While across surgical oncology, early recurrence is associated with poorer median OS compared to late recurrence,4 this will remain unknown for the IMBrave050 for at least a few more years. Cross-over and subsequent lines of therapy will further muddy the waters due to confounding effects of additional treatments postrecurrence and nononcological deaths associated with underlying liver disease. Patient expectations are however vastly different between those who have undergone curative intent surgical resection and ablation ("Can I prevent the cancer from coming back?") and those who are treated with palliative intent for advanced disease ("How long will I live?). Significant improvements in recurrence-free survival along with an acceptable safety profile have established the use of atezolizumab and bevacizumab as adjuvant therapy for high-risk HCCs but extended follow-up is required to adequately determine longevity and effects on OS. Hepatic arterial infusion chemotherapy (HAIC) is used in some Asian countries as local chemotherapy delivered directly to the liver through the supplying hepatic artery. In a phase III RCT (Postoperative adjuvant HAIC with FOLFOX in hepatocellular carcinoma with microvascular invasion: A multicenter, phase III, randomized study), Li et al observed better median disease-free survival for patients with HCCs and microvascular invasion who underwent HAIC than with surveillance (20.3 vs. 10.0 mo, HR 0.59, 95% CI: 0.43–0.81, p = 0.001), without significant OS benefit (HR 0.64, 95% CI: 0.36–1.14, p = 0.130).6 The study mandates a singular high-risk factor (microvascular invasion) and does not account for other known high-risk factors for recurrence (eg, tumor size, tumor differentiation, and number). FOLFOX is delivered over 2 cycles 4–6 weeks after surgery, and each cycle (4–5 wk apart) requires that the patient be bedbound for 3 consecutive days. The femoral artery catheter required for local chemotherapy infusion in the study can be restrictive for the patient, and there are potential adverse effects, including bleeding, vascular thrombosis, and distal ischemia, associated with the invasive procedure and prolonged placement of a temporary catheter. The practical utility of HAIC as adjuvant therapy is unclear, especially if other efficacious adjuvant therapies are available. There is scope for further research in exploring alternative chemotherapy regimens and comparisons with ICI and targeted therapy. LOCO-REGIONAL THERAPY IN LOCALLY ADVANCED AND METASTATIC HCC Loco-regional therapy (including TACE) is the current standard of care for intermediate-stage (BCLC B) HCC with good liver function that is not suited for resection or ablation. TACE is also frequently used for patients with limited PVT, although systemic therapy is recommended for such cases. The addition of a systemic therapy to loco-regional therapy for patients with intermediate-stage and locally advanced nonmetastatic HCC is thus an attractive proposition. The LAUNCH study compared a tyrosine kinase inhibitor (TKI) lenvatinib plus on-demand TACE to lenvatinib alone for patients with advanced HCC (macrovascular invasion and/or extrahepatic spread). In all, 44.7% of patients on LEN-TACE and 45.3% of patients on LEN had no extrahepatic disease. The median number of TACE deliveries in the LEN-TACE group was 3 (1–6). The trial demonstrated improvement in median progression-free survival (PFS) (10.6 vs. 6.4 mo, p < 0.001) and OS (17.8 vs. 11.5 mo, p < 0.001).7 While results were encouraging, the studied population was predominantly of single ethnicity (Chinese), younger patients with hepatitis B, many of whom were less than 60 years old, raising questions about its applicability to other demographics. The OS of 17.8 months compares modestly to alternative loco-regional therapies such as that reported by the DOSISPHERE-01 trial, where personalized dosimetry with selective internal radiation therapy, with yttrium 90, delivered OS of 24.8 months.8 Of note, DOSISPHERE-01 also had patients with larger tumors, and its inclusion criteria mandated that at least 1 lesion be 7 cm and above, while LAUNCH had 27.6% of tumors less than 5 cm in diameter. Nevertheless, the results of this RCT will be highly impactful, and we can expect wide adoption of TACE plus lenvatinib not only in locally advanced (PVT with no metastases) and metastatic HCC but also in earlier stage intermediate-stage HCC (although such patients were not enrolled in the trial). There will also be scope for other combinations of loco-regional therapy with other systemic therapies. SYSTEMIC THERAPY FOR LOCALLY ADVANCED AND METASTATIC HCC There has been significant enthusiasm with the use of immunotherapy plus a targeted therapy for advanced tumors following the success of the IMBrave150 RCT for advanced HCC in 2019, which demonstrated the utility of combining atezolizumab (anti–PD-L1) with bevacizumab (VEFR inhibitor) compared to sorafenib (TKI). CARES-310 is a phase III RCT combining an anti–PD-1 (camrelizumab) with a small molecule TKI (rivocernib, also known as apantinib) compared with sorafenib in unresectable HCC (BCLC B and C) and demonstrated an improved median PFS (5.6 vs. 3.7 mo, HR 0.52, 95% CI: 0.41–0.65, p < 0.0001) and OS (22.1 vs. 15.2 mo, HR 0.62, 95% CI: 0.49–0.80, p < 0.0001).9 CARES-310 used a comparator drug that has previously already been proven inferior to an ICI plus VEFR inhibitor combination. The combination therapy of camrelizumab plus rivocernib enters an increasingly competitive field of first-line systemic therapy for advanced HCC (atezolizumab plus bevacizumab, durvalumab plus tremelimumab, lenvatinib, and sorafenib). The combination of a TKI with an ICI in advanced HCC is an attractive proposition as the combination acts on different therapeutic targets and hopefully acts synergistically and in this respect, the LEAP-002 is a significant negative trial.10 The LEAP-002 compares the combination of lenvatinib (TKI) plus pembrolizumab (anti–PD-1) over lenvatinib alone but failed to meet its primary end point of improving median OS (21.2 vs. 19.0 mo, HR 0.84, 95% CI: 0.71–1.00, p = 0.023) and PFS (8.2 vs. 8.0 mo, HR 0.87, 95% CI: 0.73–1.02, p = 0.047). Lenvatinib has proven efficacy and is currently already used as first-line therapy in advanced HCC. It remains to be seen if lenvatinib has broader application as we await further research, including the LEAP-012 study, which examines the synergy of chemoembolization with lenvatinib plus pembrolizumab. CONCLUSION A major drawback with systemic therapeutics for HCC has been the absence of validated predictive biomarkers, and in this regard, objective response rates with systemic therapy for HCC still fall short of other common cancers with validated predictive biomarkers. Nevertheless, 2023 remains a windfall year for HCC treatment. Two-phase III RCTS in adjuvant therapy after curative intent resection or ablation in HCC have met their primary end points in 2023. In addition, there has also been a positive readout for a loco-regional therapy plus systemic therapy phase III RCT. Another systemic therapy trial of ICI plus TKI has also been positive. Treatment for HCC has begun to come of age in 2023, and we look forward to multiple therapeutics being approved for all stages of HCC. Concurrent or sequential multi-modality treatments, which have been associated with better survival outcomes, will also take an increasingly important role in the management of HCC.11 In 2023, we see the advent of mono-ethic trials that provide novel insights into a population that is distinct from Western populations. Further improvements in clinical outcomes will have to come from improved molecular profiling of HCC and developments in deciphering tumor heterogeneity to provide more precise therapeutic targets that can better aid patient selection.